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Autologous IC9-CAR19 T cells in Treating Patients with Recurrent Acute Lymphoblastic Leukemia

Trial Status: Active

This phase I trial studies the side effect of autologous inducible caspase 9 chimeric antigen receptor targeting CD19 antigen (iC9-CAR19) T cells in treating patients with acute lymphoblastic leukemia that has come back. IC9-CAR19 T cells combines antibodies and T cells. Antibodies are proteins that protect the body from disease caused by bacteria or toxic substances and by stopping them from growing. T cells are special infection fighting blood cells that can kill other cells, including cancer cells or cells that are infected.

Inclusion Criteria

  • CELL PROCUREMENT: Written informed consent for procurement signed by subject or legal guardian of a pediatric subject and Health Insurance Portability and Accountability Act (HIPAA) authorization for release of personal health information
  • CELL PROCUREMENT: Pediatric subjects (weight must be >= 10 kg)
  • CELL PROCUREMENT: Karnofsky score > 60% if >= 16 years old or Lansky performance score of greater than 60% if < 16 years old
  • CELL PROCUREMENT: Relapsed or refractory precursor B cell ALL: * Second or greater bone marrow relapse OR * Any bone marrow relapse >100 days after allogeneic stem cell transplant OR * Primary refractory ALL defined as no complete response after 2 cycles of a standard of care chemotherapy regimen OR * For adult subjects: first bone marrow relapse with duration of first complete response (CR) < 1 year OR CR1 duration >= 1 year and refractory to >= 1 cycle of therapy for treatment of relapse * Subjects with isolated non-central nervous system (CNS) extramedullary disease will be eligible as long as the time-of-remission criteria above for bone marrow relapses or primary refractory ALL are met and the biopsy for extramedullary disease confirms CD19 expression * For pediatric subjects: first bone marrow or isolated non-CNS extramedullary relapse refractory to 1 cycle of standard therapy for relapsed ALL * While active CNS3 leukemia will be excluded, subjects with concurrent CNS3 disease and bone marrow relapse who have responded to CNS-directed therapy prior to enrollment will be allowed to participate; intrathecal chemotherapy will be allowed to continue between lymphodepleting chemotherapy and cell infusion * Subjects with CNS2 disease and concurrent bone marrow relapse will be eligible; intrathecal chemotherapy will be allowed to continue between lymphodepleting chemotherapy and cell infusion
  • CELL PROCUREMENT: Subjects with Philadelphia chromosome (Ph)+ ALL will be eligible if they have failed >= 2 ABL tyrosine kinase inhibitors; subjects with the T315I ABL kinase point mutation will be eligible if they have failed ponatinib-containing therapy, regardless of the number of prior ABL tyrosine kinase inhibitors
  • CELL PROCUREMENT: CD19 positivity of lymphoblasts confirmed by flow cytometry or immunohistochemistry (IHC) per institutional standards
  • CELL PROCUREMENT: Life expectancy >= 12 weeks
  • CELL PROCUREMENT: Serum creatinine =< 1.5 x upper limit of normal (ULN), obtained within 72 hrs prior to procurement * For pediatric patients, adequate renal function is defined as below: ** Age: Maximum Serum Creatinine (mg/dL) ** 3 to < 6 years: =< 0.8 (male and female) ** 6 to < 10 years: =< 1 (male and female) ** 10 to < 13 years: =< 1.2 (male and female) ** 13 to < 16 years: =< 1.5 (male), =< 1.4 (female) ** 16 to < 18 years: =< 1.7 (male), =< 1.4 (female)
  • CELL PROCUREMENT: Bilirubin =< 1.5 x upper limit of normal (ULN), unless attributed to Gilbert’s syndrome, obtained within 72 hrs prior to procurement
  • CELL PROCUREMENT: Aspartate aminotransferase (AST) =< 3.0 x ULN, obtained within 72 hrs prior to procurement
  • CELL PROCUREMENT: Alanine aminotransferase (ALT) =< 3.0 x ULN, obtained within 72 hrs prior to procurement
  • CELL PROCUREMENT: Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to procurement; NOTE: females are considered of child bearing potential unless they are premenarchal, surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
  • CELL PROCUREMENT: Females and males of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 3 months after treatment discontinuation; the two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method; female participants will inform their male partners that they must use the methods of birth control required by the protocol * Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 3 months after the last dose of study therapy
  • CELL PROCUREMENT: As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures
  • CELL PROCUREMENT: Subjects currently receiving “maintenance” doses of chemotherapy are eligible and the need for intrathecal prophylaxis prior to procurement is left to the discretion of the investigator; maintenance doses of chemotherapy are defined as methotrexate =< 30 mg/m^2/week, mercaptopurine =< 100 mg/m^2/day and vincristine =< 2 mg/28 days; corticosteroid-containing maintenance therapy is permitted only if corticosteroids are administered > 14 days prior to procurement; (Note: corticosteroid use with doses at the discretion of the treating physician are allowed after procurement up to the beginning of lymphodepletion; corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically necessary e.g., to treat CRS)
  • LYMPHODEPLETION: Written informed consent for the main study signed by subject or legal guardian of a pediatric subject
  • LYMPHODEPLETION: Karnofsky score > 60% if >= 16 years old or Lansky performance score of greater than 60% if < 16 years old
  • LYMPHODEPLETION: Life expectancy >= 12 weeks
  • LYMPHODEPLETION: Subjects who have received prior therapy with murine antibodies must have documentation of absence of human anti-mouse antibodies (HAMA) prior to lymphodepletion on this study
  • LYMPHODEPLETION: Serum creatinine =< 1.5 x ULN, obtained within 72 hrs prior to lymphodepletion * For pediatric patients, adequate renal function is defined as below: ** Age: Maximum Serum Creatinine (mg/dL) ** 3 to < 6 years: =< 0.8 (male and female) ** 6 to < 10 years: =< 1 (male and female) ** 10 to < 13 years: =< 1.2 (male and female) ** 13 to < 16 years: =< 1.5 (male), =< 1.4 (female) ** 16 to < 18 years: =< 1.7 (male), =< 1.4 (female)
  • LYMPHODEPLETION: Bilirubin =< 1.5 x upper limit of normal (ULN) unless attributed to Gilbert’s syndrome, obtained within 72 hrs prior to procurement
  • LYMPHODEPLETION: Aspartate aminotransferase (AST) =< 3.0 x ULN, obtained within 72 hrs prior to procurement
  • LYMPHODEPLETION: Alanine aminotransferase (ALT) =< 3.0 x ULN, obtained within 72 hrs prior to procurement
  • LYMPHODEPLETION: Females of childbearing potential must have a negative serum pregnancy test within 72 hours prior to 72 hours prior to lymphodepletion; NOTE: Females are considered of child bearing potential unless they are premenarchal, surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months
  • LYMPHODEPLETION: Females and males of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 3 months after treatment discontinuation; the two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method; female participants will inform their male partners that they must use the methods of birth control required by the protocol
  • LYMPHODEPLETION: Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 3 months after the last dose of study therapy
  • LYMPHODEPLETION: As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures
  • LYMPHODEPLETION: Subjects currently receiving “maintenance” doses of chemotherapy are eligible and the need for intrathecal prophylaxis prior to lymphodepletion is left to the discretion of the investigator; maintenance chemotherapy is defined as methotrexate =< 30 mg/m^2/week, mercaptopurine =< 100 mg/m^2/day and vincristine =< 2 mg/28 days; for subjects who receive chemotherapy, including intrathecal chemotherapy, that does not fit this definition of maintenance chemotherapy, a two week washout between the last dose of standard of care chemotherapy and the beginning of lymphodepletion will be required
  • LYMPHODEPLETION: Subjects must have autologous transduced activated T-cells that meet the certificate of analysis (CofA) acceptance criteria
  • iC9-CAR19 CELL INFUSION: Demonstrate adequate renal and hepatic function; all screening labs to be obtained within 24 hrs prior to cell infusion
  • iC9-CAR19 CELL INFUSION: Females and males of childbearing potential must be willing to abstain from heterosexual activity or to use 2 forms of effective methods of contraception from the time of informed consent until 3 months after treatment discontinuation; the two contraception methods can be comprised of two barrier methods, or a barrier method plus a hormonal method; female participants will inform their male partners that they must use the methods of birth control required by the protocol
  • iC9-CAR19 CELL INFUSION: Male subjects with female partners must have had a prior vasectomy or agree to use an adequate method of contraception (i.e., double barrier method: condom plus spermicidal agent) starting with the first dose of study therapy through 3 months after the last dose of study therapy
  • iC9-CAR19 CELL INFUSION: As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures

Exclusion Criteria

  • CELL PROCUREMENT: Subjects with relapsed fulminant CD19+ ALL that is rapidly progressing who cannot safely delay definitive treatment for their ALL by at least 4 weeks in the opinion of the investigator
  • CELL PROCUREMENT: Lumbar puncture must be performed prior to procurement and subjects with evidence of CNS3 disease will be excluded from study entry; subjects with concurrent CNS3 disease and bone marrow relapse who have responded to CNS-directed therapy prior to enrollment/lymphodepletion will be allowed to participate; subjects with CNS2 disease and concurrent bone marrow relapse will be eligible; intrathecal chemotherapy will be allowed to continue between lymphodepleting chemotherapy and cell infusion
  • CELL PROCUREMENT: Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use if the milk is collected while the mother is being treated on study)
  • CELL PROCUREMENT: Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years
  • CELL PROCUREMENT: Subjects must not have tumor in a location where enlargement could cause airway obstruction
  • CELL PROCUREMENT: Subjects may not have an oxygen requirement as defined by pulse oximetry of < 90% on room air
  • CELL PROCUREMENT: Subjects must not have left ventricular ejection fraction of < 40% (shortening fraction < 27% for pediatric subjects) as measured by echocardiogram or multi-gated acquisition (MUGA)
  • CELL PROCUREMENT: Patients with the following systemic viral infections will be excluded: active human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), hepatitis B virus (HBV), hepatitis C virus (HCV) (tests can be pending at the time of cell procurement; only those samples confirming lack of active infection will be used to generate transduced cells); Note: to meet eligibility subjects are required to be negative for HIV antibody or HIV viral load, negative for HTLV1 and 2 antibody or polymerase chain reaction (PCR) negative for HTLV1 and 2, negative for hepatitis B surface antigen, or negative for HCV antibody or HCV viral load
  • CELL PROCUREMENT: Patients who are on treatment for other active uncontrolled infections (not referenced above) with resolution of signs/symptoms are not excluded; non-influenza, non-respiratory syncytial virus (RSV), isolated upper respiratory infections are not excluded; other active uncontrolled infections will be excluded
  • CELL PROCUREMENT: Prior to procurement current use of systemic corticosteroids at doses >= 10mg/day prednisone or its equivalent; those receiving < 10mg/day may be enrolled at discretion of investigator; (Note: corticosteroid use with doses at the discretion of the treating physician are allowed after procurement up to the beginning of lymphodepletion; corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically necessary e.g., to treat CRS) * Physiologic replacement with hydrocortisone is allowed at doses 6-12 mg/m^2/day, or equivalent
  • CELL PROCUREMENT: Received anti-CD19 antibody-based therapy OR cytotoxic chemotherapy not described as maintenance therapy within 2 weeks of procurement
  • LYMPHODEPLETION: Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use if the milk is collected while the mother is being treated on study)
  • LYMPHODEPLETION: Has a known additional malignancy that is active and/or progressive requiring treatment; exceptions include basal cell or squamous cell skin cancer, in situ cervical or bladder cancer, or other cancer for which the subject has been disease-free for at least five years
  • LYMPHODEPLETION: Subjects must not have tumor in a location where enlargement could cause airway obstruction
  • LYMPHODEPLETION: Subjects may not have an oxygen requirement as defined by pulse oximetry of < 90% on room air
  • LYMPHODEPLETION: Treatment with any investigational drug within 14 days (ie, two weeks) prior to lymphodepletion or has received any tumor vaccines within the previous five weeks prior to lymphodepletion
  • LYMPHODEPLETION: Patients with the following systemic viral infections will be excluded: active HIV, HTLV, HBV, HCV; Note: To meet eligibility subjects are required to be negative for HIV antibody or HIV viral load, negative for HTLV1 and 2 antibody or PCR negative for HTLV1 and 2, negative for hepatitis B surface antigen, or negative for HCV antibody or HCV viral load
  • LYMPHODEPLETION: Patients who are on treatment for other active uncontrolled infections (not referenced above) with resolution of signs/symptoms are not excluded; non-influenza, non-RSV, isolated upper respiratory infections are not excluded; other active uncontrolled infections will be excluded
  • LYMPHODEPLETION: Use of systemic corticosteroids at doses >= 10mg/day prednisone or its equivalent; those receiving < 10mg/day may be enrolled at discretion of investigator; (Note: Corticosteroid use with doses at the discretion of the treating physician are allowed after procurement up to the beginning of lymphodepletion) * Physiologic replacement with hydrocortisone is allowed at 6-12 mg/m2/day, or equivalent
  • iC9-CAR19 CELL INFUSION: Corticosteroid use is contraindicated following iC9-CAR19 infusion unless medically necessary e.g., to treat CRS)
  • iC9-CAR19 CELL INFUSION: Severe systemic uncontrolled disease or toxicities that develop after lymphodepletion may prompt exclusion from cell infusion at the discretion of the investigator

North Carolina

Chapel Hill
UNC Lineberger Comprehensive Cancer Center
Status: ACTIVE
Contact: Matthew C. Foster
Phone: 919-843-2447

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of autologous iC9-CAR19 T cells administered to adult and pediatric subjects with relapsed or refractory CD19+ acute lymphoblastic leukemia (ALL).

SECONDARY OBJECTIVES:

I. To identity a recommended phase 2 dose (RP2D) of iC9-CAR19 T cells in adult and pediatric subjects with relapsed or refractory CD19+ ALL.

II. To measure the survival of iC9-CAR19 T cells in vivo.

III. To determine the anti-leukemia overall response rate (ORR) mediated by autologous iC9-CAR19 T cells administered to adult and pediatric subjects with relapsed or refractory CD19+ ALL.

IV. To determine overall survival (OS) in adult and pediatric subjects with relapsed or refractory CD19+ ALL following infusion of iC9-CAR19 T cells.

V. To determine event-free survival (EFS) in adult and pediatric subjects with relapsed or refractory CD19+ ALL following infusion of iC9-CAR19 T cells.

VI. To determine relapse-free survival (RFS) in adult and pediatric subjects with relapsed or refractory CD19+ ALL following infusion of iC9-CAR19 T cells.

VII. To measure patient-reported symptom, physical function, and health-related quality of life at baseline and over time in adult subjects treated with iC9-CAR19 T cells.

TERTIARY OBJECTIVES:

I. To determine the utility of the safety switch in iC9-CAR19 T cells by allowing for administration of Rimiducid (AP1903) (0.4 mg/kg dose) to subjects with grade 4 cytokine release syndrome (CRS) or grade 3 CRS that is unresponsive to standard of care interventions (ie, does not resolve to grade 0-1 within 24 hours after 2 doses of tocilizumab, with sum of doses >= 12mg/kg) following infusion of iC9-CAR19 cells to adult and pediatric subjects with relapsed or refractory CD19+ ALL.

II. To explore whether changes observed on a brief cognitive assessment are associated with the occurrence of CRS or neurotoxicity from iC9-CAR19 T cells.

III. To explore feasibility of ocular ultrasound measurement of optic nerve sheath diameter in adult participants only, and associations with clinical grading of CAR-T-cell-related encephalopathy (CRES).

OUTLINE:

LYMPHODEPLETING REGIMEN: Patients receive fludarabine phosphate intravenously (IV) over 30 minutes on days 1-3 and cyclophosphamide IV over 1 hour on day 4.

All patients receive iC9-CAR19 T cells IV over 5-10 minutes within 2-14 days post-lymphodepletion.

After completion of study treatment, patients are followed up weekly until week 4, every 2 weeks until week 8, every 3 months for 1 year, every 6 months for 4 years, and yearly for 10 years.

Trial Phase Phase I

Trial Type Treatment

Lead Organization
UNC Lineberger Comprehensive Cancer Center

Principal Investigator
Matthew C. Foster

  • Primary ID LCCC 1541-ATL
  • Secondary IDs NCI-2016-01799, LCCC1541-ATL
  • Clinicaltrials.gov ID NCT03016377